Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/30—Halogen atoms or nitro radicals
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/38—One sulfur atom
  • C07D239/40—One sulfur atom as doubly bound sulfur atom or as unsubstituted mercapto radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/50—Three nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to substituted pyridine compounds, methods and compositions for making and using substituted pyridine compounds, and methods for preventing or treating diseases in humans or animals employing such compounds and compositions.
• Novel compounds for new therapeutic interventions are needed for many areas of medicine and disease treatment.
• chronic and acute inflammatory conditions form the basis for diseases affecting all organ systems including, but not limited to, asthma, acute inflammatory diseases, vascular inflammatory disease, chronic inflammation, atherosclerosis, angiopathy, myocarditis, nephritis, Crohn's disease, arthritis, type I and II diabetes and associated vascular pathologies.
• the incidence of these inflammatory conditions is on the rise in the population as a whole, with diabetes alone affecting 16 million people. Therefore, synthesis of novel compounds leads to new possibilities for discovery of novel therapeutic interventions.
• vascular smooth muscle cell proliferation is a common consequence of endothelial injury and is believed to be an early pathogenetic event in the formation of atherosclerotic plaques or complications related to vascular injury or as a result surgical interventions.
• Abnormal vascular smooth muscle cell (SMC) proliferation is thought to contribute to the pathogenesis of vascular occlusive lesions, including arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after organ transplantation.
• PTCA Percutaneous coronary artery intervention
• vascular occlusive lesions such as, but not limited to, arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after organ transplantation. Identification of effective therapeutics with minimal side effects will restore quality of life without requiring additional surgical procedures such as coronary artery bypass surgery.
• Glycated proteins and advanced glycation end products contribute to cellular damage, particularly, diabetic tissue injury, by at least by two major mechanisms: modulation of cellular functions through interactions with specific cell surface receptors; and alteration of the extracellular matrix leading to the formation of protein cross-links.
• AGE increases lipoprotein oxidizability and atherogenicity. Its binding to matrix proteins induces synthesis of cytokines and activates cellular messengers.
• Diseases where glycated protein and AGE accumulation is a suspected etiological factor include vascular complications of diabetes, microangiopathies, renal insufficiency and Alzheimer's disease.
• Non-enzymatic glycation i.e., the linking of proteins with glucose
• the first step in this glycation pathway involves the non-enzymatic condensation of glucose with free amino groups in the protein, primarily the epsilon-amino groups of lysine residues, forming the Amadori adducts.
• AGE advanced glycation end products
• SMC smooth muscle cell hyperplasia
• vascular procedures such as angioplasty, stent implantation and coronary artery bypass surgery.
• SMC smooth muscle cell
• Naturally occurring growth modulators many of which are derived from the endothelium, tightly control SMC proliferation in vivo. When the control becomes unregulated, a pathological state is induced in the subject.
• cancer Another major area of unwanted cellular growth, that is unchecked by the body's regulatory systems, is cancer or oncological conditions.
• Many therapies have been used and are being used in an effort to restore health or at least stop the unwanted cell growth.
• therapeutic agents can have an effect individually, but often, therapeutic regimes require combinations of different pharmacological agents with treatments such as surgery or radiation.
• the present invention is directed to novel pyridines, novel compositions comprising pyridines, and novel methods employing such pyridines and compositions.
• Disclosed herein are methods for making pyridines, compositions comprising pyridines, and methods and compositions for using pyridines.
• the pyridine compounds and compositions comprising the pyridine compounds have utility in treating and preventing a variety of diseases.
• compounds in accordance with the present invention, and compositions comprising these compounds comprise nitrogen heterocyclic compounds of formulas (I):
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• compounds in accordance with the present invention, and compositions comprising these compounds comprise nitrogen heterocyclic compounds of formula (III):
• a pharmaceutically acceptable or non-pharmaceutically acceptable salt including a pharmaceutically acceptable or non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention is directed to methods and compositions comprising compounds that have utility in treatment of pathological conditions.
• One aspect of the present invention comprises pyridines and compositions comprising pyridines in methods for treating diseases related to unwanted cellular proliferation.
• Vascular diseases such as cardiovascular diseases, organ transplant sequellae, vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis, are caused by or have collateral damage due to unwanted cellular proliferation, such as smooth muscle cell (SMC) hyperplasia.
• SMC smooth muscle cell
• At least one activity of one or more of these compounds is that the compound has the activity of affecting the synthesis of proteoglycans including induction and synthesis of proteoglycans and active fragments of proteoglycans.
• Methods comprise administration of compositions comprising compounds that have at least the activity of affecting cellular proliferation and affecting proteoglycan synthesis and activity.
• the pyridines and compositions comprising pyridines disclosed herein can be employed to prevent or to treat the aforementioned diseases.
• the present invention also comprises methods and compositions comprising pyridines described herein that have an activity associated with modulation of glycosidase enzymes and thus, affecting the substrates for such enzymes.
• Glycosidase enzymes and their activity with their substrates, such as proteoglycans or glycated proteins, are aspects of a variety of diseases such as vascular conditions, proteoglycan-associated diseases, kidney disease, autoimmune disease and inflammatory diseases.
• Pyridines described herein that have an activity that affects the concentrations of substrates of glycosidase enzymes are used in methods of treatment of such vascular, inflammatory, metastatic and systemic diseases.
• Another aspect of the present invention comprises methods and compositions comprising pyridines of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, inflammation.
• An aspect of the present invention is directed to methods and compositions comprising pyridines that are effective in inhibiting inflammation, particularly inflammation associated with the accumulation or presence of glycated proteins or AGE.
• Methods of treatment comprise administration of compositions comprising pyridines having at least the activity of modulating inflammatory reactions that are components of biological conditions including, but not limited to, vascular complications of type I and type II diabetic-induced vasculopathies, other vasculopathies, microangiopathies, renal insufficiency, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis.
• An aspect of the present invention also comprises methods and compositions for the treatment of diseases, preconditions or pathologies associated with inflammatory cytokines and other inflammation related molecules.
• Another aspect of the present invention comprises methods and compositions comprising compounds that have at least the activity of causing cellular death or a cessation of cellular activity, referred to herein as cytotoxic activity.
• This activity can be used in methods for in vitro or in vivo cytotoxicity.
• compounds having this activity can be selectively delivered to an area within a living organism to selectively kill cells in that area. Such methods are using in treating hyperproliferative cells, such as cancers, or other unwanted cellular growth or cellular activities.
• One aspect of the invention provides compositions comprising compounds that nonselectively kill cells.
• Another aspect of the invention provides compounds that selectively kill cells, for example, cells that have a particular cellular marker or other identifying characteristic such as metabolic rate or uptake of a particular compound.
• this invention also provides compositions comprising a pharmaceutically acceptable carrier and at least one compound as disclosed herein, and further comprising: optionally, a pharmaceutically acceptable auxiliary; optionally, a pharmaceutically acceptable preservative; optionally, a pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable diluent; and optionally, a pharmaceutically acceptable solvate.
• this composition can be in the form of, for example, a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash, and the like.
• this composition can further comprise an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, or any combination thereof.
• the present invention also comprises pharmaceutical compositions comprising the compounds disclosed herein. Routes of administration and dosages of effective amounts of the compounds and pharmaceutical compositions are also disclosed.
• the compounds of the present invention can be administered in combination with other pharmaceutical agents in a variety of protocols for effective treatment of disease.
• the present invention relates to drug delivering or eluting medical devices that contain or are coated with at least one compound disclosed herein.
• the medical device suitable for use with the compounds of the present invention include, but are not limited to, stents and other medical devices that can provide a substrate for delivery of at least one compound.
• compositions and methods for microarray devices comprise compositions and methods for microarray devices.
• microarray devices and methods comprise a variety of microarrays that may be used, for example, to study and monitor gene expression in response to treatment with the compounds of the present invention.
• the microarrays may comprise nucleic acid sequences, carbohydrates or proteins that are determinative for specific cells, tissues, species, disease states, prognoses, disease progression, or any other combination of molecules that can be used to determine an effect of one or more of the compounds of the present invention.
• Other aspects of the present invention comprise methods using databases and computer applications.
• novel pyridine compounds and novel compositions comprising pyridine compounds are described herein.
• compounds in accordance with the present invention, and compositions comprising these compounds comprise nitrogen heterocyclic compounds of formula (IIIi):
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Y 1 and Y 2 can be —(CH 2 )n- wherein n is 0, that is, R 1 and R 2 can be bonded directly to the pyridine core.
• the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Another aspect of the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Another aspect of the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Y 1 can be —(CH 2 )n- wherein n is 0, that is, R 1 can be bonded directly to the pyridine core.
• R 5 can be methyl or hydrogen.
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Still another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• R 4 can be selected from
• X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , CH(OCOCH 2 CH 2 CO 2 H), or CH(OH);
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Still another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Yet another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Yet another aspect of the present invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• R 1 can be selected from or
• X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , CH(OCOCH 2 CH 2 CO 2 H), or CH(OH);
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• R 1 can be selected from
• X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , CH(OCOCH 2 CH 2 CO 2 H), or CH(OH);
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• R 1 can be selected from
• X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , CH(OCOCH 2 CH 2 CO 2 H), or CH(OH);
• the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• n and m can be independently an integer from 0 to 2, inclusive; and R 11 and R 12 , in each occurrence, can be selected independently from OCF 3 , OMe, Cl, F, SO 2 Me, CF 3 , Me, COMe, CONHMe, NHSO 2 Me, SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 , CONH 2 , CONMe 2 , CO 2 Me, —OCH 2 O—, or OH.
• Yet another aspect of this invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Still another aspect of this invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Still another aspect of this invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• Yet another aspect of this invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
• halogen or ‘halo’ includes fluorine, chlorine, bromine, or iodine.
• alkyl group is used to refer to both linear and branched alkyl groups.
• exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, and the like.
• an alkyl group has from 1 to 10 carbon atoms.
• all structural isomers of a given structure for example, all enantiomers and all diasteriomers, are included within this definition.
• propyl is meant to include n-propyl and iso-propyl
• butyl is meant to include n-butyl, iso-butyl, t-butyl, sec-butyl, and so forth.
• Haloalkyl is a group containing at least one halogen and an alkyl portion as define above. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. Exemplary haloalkyl groups include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, trilfluoromethyl, and the like. Unless otherwise specified, a haloalkyl group has from 1 to 10 carbon atoms.
• acyl is used to refer to an H—CO— or an alkyl-CO— group, where alkyl is defined herein.
• exemplary acyl groups include, but are not limited to, acetyl, propionyl, iso-propionyl, tert-butionyl, and the like.
• Cycloalkyl group refers to a cyclic alkyl group which may be mono or polycyclic.
• exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
• a cycloalkyl group has from 3 to 10 carbon atoms.
• Alkoxy refers to an —O(alkyl) group, where alkyl is as defined above. Therefore, unless otherwise specified, all isomers of a given structure are included within a definition. Exemplary alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, and the like. Unless otherwise specified, an alkoxy group has from 1 to 10 carbon atoms.
• Alkoxyalkyl is an alkyl group with an alkoxy substituent, where alkoxy and alkyl groups are as defined above.
• exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, isopropoxymethyl isopropoxyethyl, isopropoxypropyl, t-butoxymethyl, t-butoxyethyl, t-butoxypropyl, and the like.
• an alkoxyalkyl group typically has from 1 to 10 carbon atoms.
• Haloalkoxy is an alkoxy group with a halo substituent, where alkoxy and halo groups are as defined above.
• exemplary haloalkoxy groups include chloromethoxy, trichloroethoxy, trifloroethoxy, perfluoroethoxy (—OCF 2 CF 3 ), trifluoro-t-butoxy, hexafluoro-t-butoxy, perfluoro-t-butoxy (—OC(CF 3 ) 3 ), and the like.
• an haloalkoxy group typically has from 1 to 10 carbon atoms.
• Alkylthio refers to an —S(alkyl) goup, where alkyl group is as defined above.
• alkyl groups include methylthio, ethylthio, propylthio, butylthio, iso-propylthio, iso-butylthio, and the like. Unless otherwise specified, an alkylthio group typically has from 1 to 10 carbon atoms.
• Alkylsulfonyl refers to a —SO 2 (alkyl) group, where alkyl group is as defined above.
• alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and the like. Unless otherwise specified, an alkylsulfonyl group typically has from 1 to 10 carbon atoms.
• Alkenyl is an unsaturated aliphatic group containing a C ⁇ C double bond.
• alkenyl groups include ethenyl, propenyl, prop-1-enyl, isopropenyl, butenyl, but-1-enyl, isobutenyl, pentenyl, pent-1-enyl, hexenyl, pent-2-enyl, 2-methyl-but-2-ene, 2-methyl-pent-2-enyl and the like.
• an alkenyl group typically has from 2 to 10 carbon atoms.
• Alkynyl is an unsaturated aliphatic group containing a C ⁇ C triple bond.
• exemplary alkynyl groups include ethenyl, propynyl, prop-1-ynyl, butynyl, butaynyl and the like. Unless otherwise specified, an alkynyl group typically has from 2 to 10 carbon atoms.
• Aryl is optionally substituted monocylic or polycyclic aromatic ring system of 6 to 14 carbon atoms.
• exemplary groups include phenyl, naphthyl and the like. Unless otherwise specified, an aryl group typically has from 6 to 14 carbon atoms.
• Aralkyl is an alkyl group with an aryl substituent, where alkyl and aryl groups are as defined above.
• exemplary aralkyl groups include, but are not limited to, benzyl, phenethyl (for example, 2-phenethyl), phenylpropyl (for example, 3-phenylpropyl), naphthylmethyl (for example, 1-naphthylmethyl and 2-naphthylmethyl) and the like.
• Heteroaryl is an aromatic monocyclic or polycyclic ring system of 4 to 10 carbon atoms, having at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >NH or NR, and the like, wherein R is a substituted or unstubstituted alkyl, aryl, or acyl, as defined herein.
• >NH or NR are considered to be included when the heteroatom or heterogroup can be >N—.
• heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furanyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, 1,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl and the like.
• a heteroaryl group typically has from 4 to 10 carbon atoms.
• the heteroaryl group can be bonded to the pyrimidine core structure at a ring carbon atom, or, if applicable for a N-substituted heteroaryl such as pyrrole, can be bonded to the pyrimidine core structure through the heteroatom that is formally deprotonated to form a direct heteroatom-pyrimdine ring bond.
• Heterocyclyl is a non-aromatic saturated monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO.
• exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl and the like.
• a heterocyclyl group typically has from 2 to 10 carbon atoms.
• a heterocyclyl group can be bonded through a heteroatom that is formally deprotonated or a heterocyclyl group can be bonded through a carbon atom of the heterocyclyl group.
• Carboxylic acid or its derivatives may be amides or esters.
• Exemplary carboxylic acid groups include CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh, COOH, COOCH 3 , COOC 2 H 5 or COOC 3 H 7 .
• Cyclic amines means nitrogen containing heteroaryl or heterocyclyl groups.
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• compounds according to the present invention can have the formula:
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• compounds according to the present invention can have the formula:
• a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
• substituents Y 1 , R 1 , Y 2 , R 2 , R 3 and R 4 can be selected according to the following listings, wherein each substituent is defined in Table 1.
• the substituent Y 1 and Y 2 can be selected independently from Y A , Y B , Y C , Y D , Y E , Y F , Y G , Y H , Y I , or Y J .
• the substituent R 1 can be selected independently from R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 1G1 , R 1G2 , R 1G3 , R 1G4 , R 1G5 , R 1H1 , R 1H2 , R 1H3 , R 1H4 , R 1H5 , R 1I , R 1J , R 1K , R 1L , R 1M , R 1N , R 1O , R 1P , R 1Q .
• the substituent R 2 can be selected independently from R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2G1 , R 2G2 , R 2G3 , R 2G4 , R 2G5 , R 2H1 , R 2H2 , R 2H3 , R 2H4 , R 2H5 , R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O , R 2P , or R 2Q .
• the moieties Y 1 R 1 and Y 2 R 2 can be selected independently from YR A , YR B , YR C , YR D , YR E , YR F , YR G , YR H , YR I , YR J , or YR K , as defined herein.
• the substituent R 3 can be selected independently from R 3A , R 3B , R 3C , R 3D , R 3E , R 3F , R 3G , R 3H , R 3I , R 3J , R 3K , R 3L , R 3M , R 3N , R 3O , R 3P1 , R 3P2 , R 3P3 , R 3P4 , R 3P5 , R 3Q1 , R 3Q2 , R 3Q3 , R 3Q4 , R 3Q5 , R 3R , R 3S , R 3T , R 3U , or R 3V .
• the substituent R 4 can be selected independently from R 4A , R 4B , R 4C , R 4D , R 4E , R 4F , R 4G , R 4H , R 4I , R 4J , R 4K , R 4L , R 4M , R 4N , R 4O , R 4P1 , R 4P2 , R 4P3 , R 4P4 , R 4P5 , R 4Q1 , R 4Q2 , R 4Q3 , R 4Q4 , R 4Q5 , R 4R , R 4S , R 4T , R 4U , or R 4V .
• the number of carbon atoms on the substituents refers to the carbon atoms on the base chemical moiety, and does not include the carbon atoms in any optional substituent. Again, unless otherwise indicated, any substituents are limited in size by the carbon atoms listed in the definitions of the subsitutents.
• Any carbocyclic ring, N-heterocyclic ring, morpholinyl, piperazinyl, thiomorpholinyl, pyrrolidinyl, or piperidinyl can be optionally substituted with at least one hydroxyl, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, or heteroaryl any of which having up to 10 carbon atoms.
• the piperazine nitrogen is optionally substituted by an alkyl, a cycloalkyl, an acyl, a haloalkyl, an alkoxyalkyl, SO 2 R 7 , SO 2 NR 7 2 , or CO 2 R 7 , wherein R 7 is independently selected from: a) an alkyl or an aryl having up to 8 carbon atoms; or b) hydrogen.
• R 1 , R 2 , R 5 , or R 6 moieties that do not constitute hydrogen, halogen, cyano, or hydroxyl can be optionally substituted with at least one group independently selected from: 1) alkyl; alkoxy; alkylthio; haloalkyl; cycloalkyls; aryl; heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; haloalkoxy; —OCH 2 O—; —OCOR 9 ; N(R 8 ) 2 ; —COR 9 ;
• R 8 in each occurrence, is independently: 1) an alkyl; a haloalkyl; a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or an aryl having up to 10 carbon atoms; or 2) hydrogen.
• R 9 in each occurrence, is independently an alkyl; a haloalkyl; an aryl; or a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; having up to 8 carbon atoms; wherein R 9 is optionally substituted with: 1) an alkyl, an alkoxy, a carboxylic acid, or a carboxylic acid ester, any of which having up to 8 carbon atoms; 2) halogen; or 3) hydroxyl; and
• R 3 or R 4 moieties that do not constitute hydrogen, halogen, cyano, or hydroxyl can be optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, —COR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; wherein R 10 , in each occurrence, is independently: 1) an alkyl or an aryl having up to 10 carbon atoms; or hydrogen.
• this invention encompasses compounds of the formula III-E, corresponding to formula III in which Y 2 is >NR 5 , and formula III-F, corresponding to formula III in which Y 1 is >NR 5 .
• Y 1 , R 1 , R 2 , R 4 , and R 5 of formulas III-E and Y 2 , R 1 , R 2 , R 4 , and R 5 III -F can be selected according to the listings of substituent definitions provided herein.
• the novel compound of the present invention encompasses any one of the following compounds, and any combination of the following compounds, including salts of the following compounds: [2-(3-methanesulfonyl-phenyl)-6-morpholin-4-yl-pyridin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; 1- ⁇ 3-[6-morpholin-4-yl-4-(4-trifluoromethoxy-phenylamino)-pyridin-2-yl]-phenyl ⁇ -ethanone; (2,6-di-phenyl-pyridin-4-yl)-(4-trifluoromethoxy-phenyl)-amine; [2,6-bis-(3-fluoro-phenyl)-pyridin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; 1-[3-(4-hydroxy-6′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]
• compounds provided herein may be chiral or achiral, or they may exist as racemic mixtures, diastereomers, pure enantiomers, a prodrug, a tautomer, or any mixture thereof.
• chiral compounds separate enantiomers, separate diastereomers, and any mixture of enantiomers, diastereomers, or both are encompassed herein.
• the present invention also encompasses any combination of compounds provided herein, including any salts, including pharmaceutically acceptable or non-pharmaceutically acceptable salts, or any mixture thereof.
• pharmacologically acceptable salt or “pharmacologically acceptable” salt refers generally to a salt or complex of the compound or compounds in which the compound can be either anionic or cationic, and have associated with it a counter cation or anion, respectively, that is generally considered suitable for human or animal consumption.
• a pharmaceutically acceptable salt can refer to a salt of a compound disclosed herein that forms upon reaction or complexation with an acid whose anion is generally considered suitable for human or animal consumption.
• pharmacologically acceptable salts include salts with organic acids or inorganic acids.
• pharmacologically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, propionate, lactate, maleate, malate, succinate, tartarate, and the like.
• Salts may also be formed by deprotonating acid moiety of compound, such as a carboxylic acid moiety, OH, or NH, and the like, using a base such as an organic base, an inorganic base, an organometallic base, a Lewis base, a Br ⁇ nsted base, or any mixture thereof.
• suitable pharmaceutically acceptable salts can include alkali metal salts, alkaline earth metal salts, or salts with organic basis, and the like.
• alkali metal salts include, but are not limited to, sodium and potassium salts
• examples of salts with organic basis include, but are not limited to, meglumine salts, and the like.
• the pharmacologically acceptable salts may be prepared by conventional means. Additional examples of pharmaceutically acceptable salts, and methods of preparing such salts, are found, for example, in Berg et.al., J. Pharma. Sci, 66, 1-19 (1977).
• this invention also provides a composition comprising at least one compound as disclosed herein, including a composition comprising a pharmaceutically acceptable carrier and at least one compound as disclosed herein.
• the at least one compound can be present as a neutral compound, as a salt, or as any combination thereof.
• This invention also encompasses a composition comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof.
• this invention encompasses a pharmaceutical composition, comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch.
• a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof, wherein the pharmaceutical composition is in the form of a tablet, a capsule,
• this invention encompasses a pharmaceutical composition, comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; and further comprising an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, or any combination thereof.
• a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof
• Another aspect of this invention is directed to using the compounds and compositions disclosed herein in a method of treating a condition or disease state mediated by the low expression of Perlecan, comprising administering an amount of at least one compound as disclosed herein, effective to induce Perlecan expression.
• a further aspect of this invention is directed to using the compounds and compositions disclosed herein in a method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, comprising administering an effective amount of at least one compound as disclosed herein.
• One more aspect of the present invention provides a process for the preparation of the compounds of general formulas (I) and (III).
• substituted pyridine analogs can be prepared generally using standard synthetic methods and employing starting materials that are readily available commercially.
• the general synthetic methods provided will be readily understood by one of ordinary skill in the art, and any variations needed for a particular species are simple and readily understood and appreciated by the skilled artisan.
• variable chemical moieties refer to any chemical group consistent with the description of the compound and substituents on that compound as provided herein.
• palladium catalyst refers to a suitable palladium catalyst, typically a complex of Pd(0) or Pd(II), including but not limited to, such compounds as palladium(0) tetrakis-(triphenylphosphine), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, that is known to catalyze the reaction shown.
• the catalytic system can also include monodentate or chelating ligands, examples of which include, but are not limited to, 2,2′-bis(diphenyl phosphino)-1,1-binapthyl, tri-tert-butyl phosphine, and the like, and can also include a base such as sodium carbonate, sodium or potassium tert-butoxide, or potassium phosphate.
• monodentate or chelating ligands examples of which include, but are not limited to, 2,2′-bis(diphenyl phosphino)-1,1-binapthyl, tri-tert-butyl phosphine, and the like, and can also include a base such as sodium carbonate, sodium or potassium tert-butoxide, or potassium phosphate.
• Transition metal catalyzed reactions can be typically carried out at ambient temperature or at elevated temperatures using various inert solvents, examples of which include, but are not limited to, toluene, dioxane, DMF, N-methyl pyrrolidine, ethylene glycol, dimethyl ether, diglyme, acetonitrile, or any combination thereof.
• commonly employed reagent and catalyst pairs include, but are not limited to, aryl boronic acids and palladium(0), (Suzuki reaction, Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457).
• a compound of formula 1a was aminated with any of a variety of substituted or unsubstituted anilines to provide a compound of the formula 1b, wherein R 1 is typically an aryl group such as a substituted or unsubstituted phenyl group and Y is a leaving group, in presence of tris(dibenzylideneacetone)dipalladium(0), 1,3-bis(diphenylphosphino)propane, and sodium tert-butoxide.
• Compound 1b was converted to compound of the type 1c, where one or both of the R 2 substituents can be a substituted or unsubstituted phenyl and one of the R 2 is optionally hydrogen, by palladium-catalyzed cross-coupling of substituted or unsubstituted phenyl boronic acids.
• palladium tetrakis-(triphenyl-phosphine) was used as palladium catalyst in this reaction scheme.
• a compound of formula 2a prepared for example according to Scheme 1, was useful in further amination reactions.
• compound 2a was treated with various primary (H 2 NR 1 , as illustrated in Scheme 2) or secondary amines (HNR 1 2 , not illustrated in Scheme 2) in an appropriate solvent such as dimethylformamide, N-methyl pyrollidine, and a base such as potassium carbonate.
• primary NR 1 as illustrated in Scheme 2
• secondary amines HNR 1 2 , not illustrated in Scheme 2
• examples of secondary amines that were used include, but are not limited to, the heterocyclic compounds such as piperidine, pyrrolidine, and the like.
• R 3 in one aspect, is an aryl group such as a substituted or unsubstituted phenyl, by a palladium-catalyzed cross-coupling of substituted or unsubstituted phenyl boronic acids.
• R 3 in one aspect, is an aryl group such as a substituted or unsubstituted phenyl, by a palladium-catalyzed cross-coupling of substituted or unsubstituted phenyl boronic acids.
• palladium tetrakis(triphenylphosphine) was used as palladium catalyst in this reaction scheme.
• a compound of formula 1a which was prepared, for example, as illustrated in Scheme 1, was converted to a compound of formula 3a, Scheme 3, where R 1 represents at least one optional substituent on the aryl group, by reacting 1a with appropriately substituted or unsubstituted phenyl boronic acids.
• Compound 3a was then converted to compound 3b, wherein R 2 is an amino group, by its reaction with, for example, a primary or secondary amine or aniline, in an appropriate solvent such as dimethylformamide, N-methyl pyrollidine, and a base such as potassium carbonate.
• R 3 in one aspect, is an aryl group such as a substituted or unsubstituted phenyl, by a palladium-catalyzed cross-coupling of substituted or unsubstituted phenyl boronic acids, in the presence of a base such as potassium carbonate or sodium carbonate.
• a base such as potassium carbonate or sodium carbonate.
• tris(dibenzylideneacetone)dipalladium(0) was used as palladium catalyst in this step of the reaction scheme.
• a compound of formula 4a is converted to compound of formula 4b, where R 1 was a range of hydrocarbyl groups, such as substituted or unsubstituted alkyl or aryl groups, by the reaction of 4a with the appropriate substituted or unsubstituted primary amine (H 2 NR 1 , as illustrated in Scheme 4) or secondary amine (HNR 1 2 , not illustrated in Scheme 4), or aniline (also not illustrated in Scheme 4).
• This reaction was typically effected in a polar solvent, including but not limited to, dimethylsulfoxide, and in the presence of base, for example sodium hydride.
• compound 4b was converted to compound 4c by its reaction with a range of substituted or unsubstituted anilines H 2 NR 2 in the presence of a base and a palladium catalyst, where R 2 is typically a substituted or unsubstituted aryl group.
• R 3 in one aspect, is an aryl group such as a substituted or unsubstituted phenyl, by a palladium-catalyzed cross-coupling of substituted or unsubstituted phenyl boronic acids.
• palladium tetrakis(triphenylphosphine) was used as palladium catalyst in this reaction scheme.
• pyridines with leaving groups at the 2-, 4-, and 6-positions such as trihalogenated pyridines, were useful in preparing a number of substituted pyridines.
• 2,4,6-trichloropyridine, formula 5a was aminated using primary (H 2 NR 1 , as illustrated in Scheme 5) or secondary amines (HNR 1 2 , not illustrated in Scheme 5) to prepared the 2,6-dihalogenated pyridines of formula 5b.
• the palladium-catalyzed cross-coupling reaction of substituted or unsubstituted phenyl boronic acids with compound 5b afforded the 2,6-diarylated pyridine compounds of formula 5c.
• reaction Scheme 6 is a general reaction scheme that illustrates one aspect of how the compounds of the present invention can be prepared.
• L represents leaving group selected from halogen, aryloxy, alkylsulfinyl, alkylsulfonyl such as trifluoromethanesulfonyloxy, arylsulfinyl, arylsulfonyl, siloxy, cyano, pyrazolo, triazolo and the like, is converted to a compound of formula (I) by reacting with the compound GR 2 wherein G represents hydrogen, NH 2 , NHR 5 , OH, SH, B(OH) 2 , Li or MgZ where Z represents halogen; when G represents NR 5 , R 2 and R 5 together may also form an optionally substituted cyclic ring along with adjacent N atom, which may be optionally containing one or more hetero atoms selected from oxygen, nitrogen or sulfur; and all other symbols
• the reaction is carried out in presence of solvent such as acetone, dimethylformamide (DMF), dimethylacetamide (DMA), benzene, toluene and the like.
• solvent such as acetone, dimethylformamide (DMF), dimethylacetamide (DMA), benzene, toluene and the like.
• the temperature of the reaction may be in the range of about 25° C. to about 150° C.
• the duration of the reaction is variable, but can be, for example, in the range of about 2 to about 48 hours.
• typical reactions and reaction conditions that can be used to prepare the novel compounds of this invention include, but are not limited to, for example, the reactions provided in Scheme 7.
• typical reaction conditions include, but by no means are limited to the following. These conditions are provided solely as a guide for one of ordinary skill, such that the skilled artisan will readily appreciate how modifications of these conditions can selected according to the particular chemical moiety being substituted at the pyridine core.
• Examples of conditions include, but are not limited to: A, acetonitrile, sodium carbonate (0.4 M), tetrakis(triphenylphosphine)palladium(0), reflux; B, (PhCH ⁇ CHCOCH ⁇ CHPh) 3 Pd 2 (tris(dibenzylidineacetone)dipalladium(0)), sodium-tert-butoxide, 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (CAS number 331465-71-5), toluene, reflux; C, (PhCH ⁇ CHCOCH ⁇ CBPh) 3 Pd 2 (tris(dibenzylidineacetone)dipalladium(0)), 1,3-bis(diphenylphosphino)propane, sodium-tert-butoxide, toluene, reflux; D, dimethoxy ethane, sodium carbonate (2 M), tetrakis(triphenylphos
• the intermediate was coupled with a boronic acid under Suzuki conditions using a Pd catalyst [for example, Pd(PPh 3 ) 4 ] in the presence of a base (for example, Na 2 CO 3 or K 2 CO 3 ) in a polar solvent under thermal conditions, either traditional thermal conditions or under microwave heating conditions.
• a Pd catalyst for example, Pd(PPh 3 ) 4
• a base for example, Na 2 CO 3 or K 2 CO 3
• a polar solvent for example, either traditional thermal conditions or under microwave heating conditions.
• the monochloropyridine was aminated using Buchwald-Hartwig conditions using a Pd catalyst [for example, Pd(OAc) 2 ] and a ligand such as BINAP, under basic conditions (for example, using potassium tert-butoxide) in a toluene solvent, in a laboratory microwave (at about 150° C.).
• the intermediate was coupled with a boronic acid under Suzuki conditions using a Pd catalyst [for example, Pd(PPh 3 ) 4 ] in the presence of a based (for example, Na 2 CO 3 ) in a polar solvent at reflux.
• a Pd catalyst for example, Pd(PPh 3 ) 4
• the intermediate was aminated with the heterocyclic amine using excess amine or in DMF/K 2 CO 3 at reflux.
• the intermediate was alkylated using a base followed by an alkyl halide.
• Scheme 11 illustrates the preparation of 4-aryl substituted pyridines that were synthesized under standard Suzuki conditions as described in various other reaction schemes disclosed herein.
• Compound 11a is drawn to indicate that the chemistry could potentially be expanded if further functionality was in the 2-position (A), the 6-position (B), or both the 2- and 6-positions.
• Compound 11a was appropriately halo-substituted, then other Pd-mediated coupling/amination chemistry could be employed to yield substituted 2,4,6-substituted pyridines.
• Scheme 12 illustrates the typical preparation of 2,6-di-aryl substituted pyridines (12b) that were prepared under standard Suzuki conditions (“a”) as described the various reaction schemes disclosed herein.
• compound 12a was aminated under microwave conditions (thermal) in the presence of a base such as potassium tert-butoxide (conditions “b”). The intermediate compound shown could then be subjected to conditions “a” as illustrated.
• 2,6-dibromopyridine was used as the starting compound
• 2,6-dichloropyridine was used as the starting compound.
• X can be at least Cl, Br, or I, as indicated in the compound 12a.
• 12a is shown indicating a further functionality located at the 4 (C) position, which also occurs in compounds 12b and 12c.
• C is halide
• other Pd-mediated coupling/amination chemistry could be employed to yield substituted 2,4,6-substituted pyridines.
• prodrugs comprise functional derivatives of the claimed compounds which are capable of being enzymatically activated or converted into the more active parent form.
• administering encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wihnan, 14 Biochem. Soc. Trans. 375-82 (1986); Stella et al., Prodrugs: A Chemical Approach to Targeted Drug Delivery in Directed Drug Delivery, 247-67 (1985).
• the prodrugs of present invention include, but are not limited to, derivatives of carboxylic acid, sulfonamide, amine, hydroxyl, and the like, including other functional groups and including any combination thereof.
• this invention provides a pharmaceutical composition, comprising a compound any of the formulas shown above, including any combination thereof, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, and the like, or any combination thereof.
• this invention affords a method of treating a condition or disease state mediated by the low expression of Perlecan, comprising administering at least one compound as disclosed herein, in an amount effective to induce Perlecan expression.
• this invention also provides a method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, comprising administering an effective amount of at least one compound as disclosed herein.
• One aspect of the present invention comprises methods and compositions comprising the compounds of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, unwanted cellular proliferation occurring or are the result of cellular proliferation.
• vascular diseases such as cardiovascular diseases, organ transplant sequellae, vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis, are caused by or have collateral damage due to unwanted cellular proliferation.
• One aspect of the present invention relates to methods and compositions for the treatment and prevention of SMC proliferation, such compositions comprising compounds having cellular antiproliferative activity. These compounds and compositions comprising such compounds are referred to as antiproliferative compounds or compositions. At least one activity of one or more of these compounds is that the compound has the activity of affecting the synthesis of proteoglycans including induction and synthesis of proteoglycans and active fragments of proteoglycans. Thus, one aspect of the activity of one or more of the compounds and compositions of the present invention comprise molecules that induce HSPG production and that regulate SMC proliferation.
• assays that can be used to determine the activity of the compounds of the present invention include other methods for measuring the induction of perlecan synthesis. For example, in one assay, perlecan is induced in cells by certain inducers, and the response is measured. Compounds of the present invention are then added to a replicate assay and the effect on perlecan induction is determined. Using such methods, compounds are determined that can either inhibit perlecan, elevate induction of perlecan, or have no effect at all. Those compounds that are effective as therapeutic agents can then be used in animals, humans or patients with cellular proliferation disease aspects, such as vascular-associated diseases or SMC (smooth muscle cell) proliferation pathologies.
• SMC smooth muscle cell proliferation pathologies.
• Another assay for determining compounds having SMC effects comprises adding a composition suspected of effecting SMC proliferation to smooth muscle cells in growth medium or serum-free medium.
• the change in cell proliferation can be measured by methods known to those skilled in the art, such as incorporation of labeled nucleotides into dividing cells' DNA, and compared to the proliferation of cells which are not treated with the compound.
• Other measurements include directly determining levels of HSPG synthesis by measuring the amount or change in amount of HSPG such as with ELISA for HSPGs, and compared to the amount of HSPG synthesis in untreated cells.
• Other indirect or direct measurements are contemplated by the present invention and are known to those skilled in the art.
• such methods include, but are not limited to, measurement of RNA levels, RT-PCR, Northern blotting, Western blotting promoter-based assays to identify compounds that affect one or more proteoglycans and assays for proteoglycan biological activity shown by recombinant proteins, partially purified proteins, or lysates from cells expressing proteoglycans in the presence or absence of compounds of interest.
• An assay for identifying and determining an activity of one or more of the compounds of the present invention comprises identifying compounds that interact with the promoter regions of a gene, or interact and effect proteins that interact with the promoter region, and are important in the transcriptional regulation of the protein's expression.
• the method comprises a vector comprising regulatory sequences of the perlecan gene and an indicator region controlled by the regulatory sequences, such as an enzyme, in a promoter-reporter construct.
• the protein product of the indicator region is referred to herein as a reporter enzyme or reporter protein.
• the regulatory region of the sequence of perlecan comprises a range of nucleotides from approximately ⁇ 4000 to +2000 wherein the transcription initiation site is +1, alternatively, from ⁇ 2500 to +1200, and still alternatively, from ⁇ 1500 to +800 relative to the transcription initiation site.
• Cells are transfected with a vector comprising the promoter-reporter construct and then treated with one or more compositions comprising at least one compound of the present invention.
• the transfected cells are treated with a composition comprising a compound suspected of effecting the transcription of perlecan and the level of activity of the perlecan regulatory sequences are compared to the level of activity in cells that were not treated with the compound.
• the levels of activity of the perlecan regulatory sequences are determined by measuring the amount of the reporter protein or determining the activity of the reporter enzyme controlled by the regulatory sequences.
• An increase in the amount of the reporter protein or the reporter enzyme activity shows a stimulatory effect on perlecan, by positively effecting the promoter, whereas a decrease in the amount or the reporter protein or the reporter enzyme activity shows a negative effect on the promoter and thus, on perlecan.
• the present invention comprises methods and compositions that can be used with gene therapy methods and composition, such as those gene therapy methods comprising administering compositions comprising nucleic acids that effect the synthesis or expression of HSPGs, particularly perlecan.
• gene therapy methods and composition such as those gene therapy methods comprising administering compositions comprising nucleic acids that effect the synthesis or expression of HSPGs, particularly perlecan.
• Such methods and compositions are taught in U.S. patent application Ser. No. 10/091,357, incorporated herein by reference.
• the present invention comprises methods and compositions for mediating proteoglycan synthesis, expression and for the maintenance of SMC in a quiescent state.
• Methods and compositions of the present invention comprise treatment and prevention of vascular diseases and pathologies related to cellular proliferation, such as SMC proliferation.
• Such methods and compositions comprise methods for inhibition of SMC growth and proliferation, and for induction of quiescence in smooth muscle cells.
• aspects of the present invention comprise methods and compositions for inducing proteoglycan synthesis, particularly HSPG synthesis and expression including, but not limited to, the induction of HSPGs such as syndecans, glypicans, and perlecans, and preferably perlecan synthesis and gene expression.
• HSPG HSPG synthesis and expression
• Perlecan is a major extracellular HSPG in the blood vessel matrix. It interacts with extracellular matrix proteins, growth factors and receptors. Perlecan is also present in basement membranes other than blood vessels and in other extracellular matrix structures.
• the activities of the compounds included in the present invention affect cells or tissues to increase the synthesis of proteoglycans by those cells or tissues or can act directly upon one or more proteoglycans to modulate the biological activity or to increase the biological stability of the proteoglycan itself, for example, of the protein perlecan. Activities also included herein are ones that increase the biosynthesis of one or more proteoglycans by increasing the transcription of the poteoglycan gene, increasing the biological stability of the proteoglycan mRNA or increasing the translation of proteoglycan mRNA into protein. Further activites include activities of compounds that can block or decrease the effects of agents or proteins that inhibit the activity of proteoglycans.
• the present invention comprises methods and compositions for the treatment and prevention of smooth muscle cell proliferation, including vascular occlusive pathologies.
• Such methods comprise administration of compositions comprising compounds capable of inhibiting SMC proliferation, such as compositions comprising compounds disclosed herein that inhibit SMC proliferation.
• Administration of such compounds that are effective in inhibiting SMC proliferation are administered to humans and animals suspected of having or who have, for example, vasculopathy or who have undergone angioplasty or other procedures damaging to the endothelium.
• Effective amounts are administered to such humans and animals in dosages that are safe and effective, including, but not limited to, the ranges taught herein.
• Routes of administration include, but are not limited to, those disclosed herein.
• compositions comprising such compounds may be used in conjunction with other therapeutic agents or in methods comprising steps such as altered patient activities, including, but not limited to, changes in exercise or diet.
• the present invention also comprises methods and compositions comprising compounds described herein that have an activity associated with modulation of glycosidase enzymes and thus, effecting the substrates for such enzymes.
• Glycosidase enzymes and their activity with their substrates are aspects of a variety of diseases such as vascular conditions, including those conditions discussed supra, proteoglycan-associated diseases, supra, associated diseases with vascular components, including but not limited to, kidney disease, ischemic heart disease, cardiovascular disease, generalized vascular disease, proliferative retinopathy, macroangeopathy, inflammatory diseases, and metastatic diseases such as cancer, cellular proliferative conditions, and solid and blood borne tumors, or other oncological conditions.
• Compounds described herein that have an activity that affects the concentrations of substrates of glycosidase enzymes are used in methods of treatment of such vascular, inflammatory, metastatic, and systemic diseases.
• Compounds or compositions comprising such compounds that are effective in modulating glycosidase enzyme activity are useful in treating and/or preventing cancer including, but not limited to, malignant and non-malignant cell growth, and the like.
• the compounds disclosed herein are useful in modulating heparanase activity or the activity of other glycosidases as a means for treating and preventing autoimmune diseases.
• the inhibition of heparanase or the activity of other glycosidases using the compounds of the present invention finds utitlity in treating arthritis and other autoimmune diseases. More specifically, the compounds of the present invention are useful in the treatment or prophylaxis of at least one autoimmune-related disease in a cell, tissue, organ, animal, or patient including, but not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/ admireer's granulomatosis, sarcoidosis, orchit
• Compounds having heparanase activity inhibition can be determined using assays such as those disclosed in U.S. patent application Ser. No. 09/952,648, which is incorporated herein in its entirety.
• assays which are used for measurement of cellular and enzymatic activities, both qualitatively and quantitatively, and in methods for diagnosing metastases, metastatic potential, and inflammatory states, are performed with and without the addition of at least one of the compounds of the present invention to determine the activity of the compound.
• Existing heparanase assays are taught in Goshen et al., 2 M OL . H UM . R EPROD.
• the present invention comprises methods and compositions for the treatment and prevention of diseases or conditions that present or result from glycosidase activity.
• Such methods comprise administration of compositions comprising compounds capable of modulating heparanase activity, such as compositions comprising compounds disclosed herein that inhibit heparanase activity.
• Administration of such compounds that are effective in modulating heparanase activity are administered to humans and animals suspected of having or who have, for example, inflammatory conditions, autoimmune disease, or diabetic vasculopathy.
• Effective amounts are administered to such humans and animals in dosages that are safe and effective, including, but not limited to, the ranges taught herein.
• Routes of administration include, but are not limited to, those disclosed herein.
• compositions comprising such compounds can be used in conjunction with other therapeutic agents or in methods comprising steps such as altered patient activities.
• One aspect of the present invention comprises methods and compositions comprising compounds of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, inflammation.
• An aspect of the present invention is directed to methods and compositions comprising compounds that are effective in inhibiting inflammation, particularly inflammation associated with the accumulation or presence of glycated proteins or AGE.
• the activity of modulating inflammation includes, but is not limited to, inhibiting inflammation and/or its associated cell activation by glycated proteins or AGE, blocking the glycation of proteins, blocking AGE interactions with receptors, blocking AGE-induced signaling or signaling-associated inflammatory responses, cytokine induction, synthesis, or release, AGE formation, or AGE cross-linking.
• the present invention also provides compositions for and methods of treatment of biological conditions including, but not limited to, vascular complications of type I and type II diabetes and atherosclerosis.
• Other inflammatory related diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, intraoccular inflammation, psoriasis, and asthma.
• the compounds of the present invention have utility in inhibiting inflammation and/or its associated cell activation by glycated proteins or AGE.
• Pharmacological inhibition of AGE-induced cell activation provides the basis for therapeutic intervention in many diseases, notably in diabetic complications and Alzheimer's disease.
• Therapeutic approaches for inhibition of AGE-induced inflammation include, but are not limited to, blocking the glycation of proteins, blocking AGE interactions with receptors, and blocking AGE-induced signaling or signaling-associated inflammatory responses.
• Compounds of the present invention that have at least the activity of modulating inflammation activity are shown in Table 4.
• the compounds shown in this Table have the activity of modulating inflammation activity as measured by the assays taught herein.
• the activity of the compounds of the present invention in inhibiting glycated protein- and AGE-induced inflammation can be determined using the assays described herein and in U.S. patent application Ser. No. 10/026,335, which is incorporated by reference herein in its entirety.
• Such assays comprise measurement of the specific activity of biological components involved in a known cellular response.
• the assays provide a measurable response in which the activity of the compounds is determined.
• One assay comprises measurement of the effects of compounds on an inflammatory response by cells to the presence of a stimulating agent.
• Yet another assay comprises endothelial cells that are stimulated by the addition of a glycated protein, the stimulating agent. The endothelial cells respond by producing specific cytokines.
• the amount of cytokines produced are determined by measurement protocols known to those skilled in the art.
• the compounds of the present invention are then added to the assay and the production of cytokines is measured. From the comparison of the assay without the compound with the assay with the compound, the biological effect of the compound can be determined.
• the compound may have an inhibitory effect, a stimulatory effect, or no effect at all.
• the amount and type of cytokine produced can be determined using immunological methods, such as ELISA assays.
• the methods of the present invention are not limited by the type of assay used to measure the amount of cytokine produced, and any methods known to those skilled in the art and later developed can be used to measure the amount of cytokines produced in response to the stimulating agent and to the compound having unknown activity.
• An aspect of the present invention comprises methods and compositions for the treatment of diseases, preconditions, or pathologies associated with inflammatory cytokines and other inflammation related molecules including, but not limited to IL-6, VCAM-1, or AGE-induced MCP-1, (monocyte chemoattractant protein 1).
• Assays for determining the activity of compounds capable of modulating inflammation include those taught in U.S. patent application Ser. Nos. 10/026,335 and 09/969,013, which are both expressly incorporated by reference in their entireties.
• the methods comprise addition of compounds of the present invention.
• the effect of the compound on the baseline response is determined by comparing the amount of cytokine produced in the presence of the stimulating agent and the amount of cytokine produced in the presence of the stimulating agent and the compound of the present invention.
• compounds that have inhibitory effects on the inflammation of the cells in the presence of glycated albumin are then used as therapeutic agents.
• One or more compounds can be added to the screening assay. Combinations or mixtures of compounds can be added. Different amounts and formulations of the compounds are added to determine the effects on the screening assay.
• the screening assay can also be used to determine stimulatory compounds or compounds that have no effects in the assay.
• the present invention comprises methods and compositions for the treatment and prevention of disease, conditions and pathologies associated with inflammation.
• Such methods comprise administration of compositions comprising compounds capable of modulating the activity of molecules associated with inflammation such as AGE or cytokines or other cellular factors, including release rates or activity, and include compositions comprising compounds disclosed herein with inflammation modulating activity.
• Administration of such compounds that are effective in modulating inflammation are administered to humans and animals suspected of having or who have inflammatory diseases, for example, diabetic-induced vasculopathies, autoimmune diseases, renal insufficiency, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis.
• Effective amounts are administered to such humans and animals in dosages that are safe and effective, including, but not limited to, the ranges taught herein. Routes of administration include, but are not limited to, those disclosed herein.
• compositions comprising such compounds can be used in conjunction with other therapeutic agents or in methods comprising steps such as altered patient activities, including, but not limited to, changes in exercise or diet.
• Tables 5-8 provide disclosure and references that relate the various physiological parameters and assays disclosed herein to general and specific diseases, disease states, and conditions.
• the references and citations provided in these tables support the specification as fully enabled for treating or modulating all the diseases or conditions encompassed herein, based on the inhibiting activity of the compounds provided in the specification, and the predictive nature of the tests provided of the disclosed uses.
• Tables 5-8 provide specific references that link the parameters measured in the key assays disclosed in the application with a specific physiology, pathophysiology, or medical condition.
• Table 5 provides scientific references that demonstrate, among other things, the connection between TNF- ⁇ and IL-6 in rheumatoid arthritis, vascular inflammation, and atherosclerosis. For example, these references demonstrate the importance of TNF inhibition in preventing rheumatoid arthritis, the therapeutic benefit of IL-6 inhibition in rheumatoid arthritis as well as its importance in preventing rheumatoid arthritis, the role of AGE in different diabetic vascular diseases, and AGE inhibition as a therapeutic strategy for vascular complications.
• Table 6 provides scientific references that demonstrate, among other things, the importance of HSPG in the prevention of atherosclerosis and diabetic vascular disease. For example, these references demonstrate that atherosclerotic vessels have reduced HSPG, and that cholesterol deposition is inversely correlated to HSPG content in the vessel.
• Table 7 also provides scientific references that demonstrate, among other things, the connection between smooth muscle cell (SMC) proliferation in contributing to restenosis and atherosclerosis.
• SMC smooth muscle cell
• these references demonstrate that: smooth muscle proliferation contributes to unstable angina and restenosis; inhibition of SMC proliferation by LRP is important for atherosclerosis prevention; and the function of the SMC inhibitor, rapamycin, in preventing restenosis and vein graft disease.
• Table 8 provides scientific references that demonstrate, among other things, the role of heparanase and TNF- ⁇ in promoting tumor angiogenesis and metastasis, as well as the use of inhibitors of heparanase and TNF- ⁇ in treating cancer.
• these references demonstrate the role of heparanase inhibitors in treating tumor angiogenesis and metastasis, the role of TNF- ⁇ as a tumor-promoting agent, and the use of TNF- ⁇ inhibitors in the treatment of cancer.
• the key assays described herein for screening the compounds in the present invention include, but are not limited to: a) the inhibition of smooth muscle cell (SMC) proliferation, that was used to identify, for example, compounds in Table 3; b) the induction of HSPG in smooth muscle cells; c) the induction of heparanase in endothelial cells; d) the inhibition of AGE-induced inflammatory response in endothelial cells as measured by IL-6 or other inflammatory cytokines, that was used to identify, for example, compounds in Table 4; and e) cytotoxicity effects of the disclosed compounds.
• SMC smooth muscle cell
• physiology, pathophysiology, or medical conditions disclosed include generically disclosed conditions and diseases such as, but are not limited to, unwanted cellular proliferation, inflammation mediated diseases, hyperproliferative diseases, and diseases involving a glycosidase.
• diseases include, but are not limited to, restenosis, vascular occlusive diseases, arthritis, cancer, and the like.
• HSPG Atherosclerosis Data show that et al, sulfated 1989; 9: 154-8 atherosclerotic vessels Ref 7 glycosaminoglycans have reduced HSPG and and cholesterol that cholesterol deposition content in normal and is inversely correlated to atherosclerotic human HSPG content in the aorta vessel Kruse R et Cholesterol-dependent Basic Res HSPG Atherosclerosis Data show that al changes of Cardiol. atherosclerotic vessels Ref 8 glycosaminoglycan September- have reduced HSPG and pattern in human aorta October that cholesterol deposition 1996; 91(5): 344-52 is inversely correlated to HSPG content in the vessel
• Smooth Restenosis 82 Review detailing the role of Dullaeus new therapeutic target 7, 1998; 98(1): 82-9 muscle cell smooth muscle et al for vascular (SMC) proliferation in restenosis Ref 10 proliferative disease proliferation and pharmacological approaches to inhibit cell cycle progression Boucher et LRP: role in vascular Science. Smooth Atherosclerosis Abstract Study shows that inhibition al wall integrity and Apr. 11, 2003; muscle cell of SMC proliferation by Ref 11 protection from 300(5617): 329-32 (SMC) LRP (lipoprotein receptor- atherosclerosis proliferation related protein) is critical for atherosclerosis prevention Marx et al Bench to bedside: the Circulation. Smooth Restenosis 852 Review highlighting the Ref 12 development of Aug.
• the compounds of the present invention can be used alone or in combination with other agents along with delivery devices to effectively prevent and treat the diseases described herein, though particular applications are found in vascular disease, and in particular, vascular disease caused by injury and/or by transplantation. Though this example focuses on vascular disease, provision of the compounds of the present invention with medical devices for treatment of the diseases and conditions capable of being treated with the compounds is contemplated by the present invention.
• balloon angioplasty is a procedure utilized to increase blood flow through an artery and is the predominant treatment for coronary vessel stenosis.
• the procedure typically causes a certain degree of damage to the vessel wall, thereby creating new problems or exacerbating the original problem at a point later in time.
• exemplary aspects of the present invention will be described with respect to the treatment of restenosis and related complications following percutaneous transluminal coronary angioplasty and other similar arterial/venous procedures, including the joining of arteries, veins and other fluid carrying conduits in other organs or sites of the body, such as the liver, lung, bladder, kidney, brain, prostate, neck and legs.
• the local delivery of a compound of the present invention and, in some aspects, along with other therapeutic agents, from a stent prevents vessel recoil and remodeling through the scaffolding action of the stent.
• the activity of compound provided, with or without other therapeutic agents helps determine for which application, to treat which disease, the coated medical device is being administered.
• compound-coated stents can prevent multiple components of neointimal hyperplasia or restenosis as well as reduce inflammation and thrombosis.
• Local administration of a compound of the present invention and other therapeutic agents to stented coronary arteries may also have additional therapeutic benefit. For example, higher tissue concentrations of the compounds of the present invention and other therapeutic agents may be achieved utilizing local delivery rather than systemic administration.
• reduced systemic toxicity may be achieved utilizing local delivery rather than systemic administration while maintaining higher tissue concentrations.
• a single procedure may suffice with better patient compliance.
• An additional benefit of combination therapeutic agent and/or compound therapy can be to reduce the dose of each of the therapeutic agents, thereby limiting toxicity, while still achieving a reduction in restenosis, inflammation and thrombosis.
• Local stent-based therapy is therefore a means of improving the therapeutic ratio (efficacy/toxicity) of anti-restenosis, anti-inflammatory, and anti-thrombotic therapeutic agents.
• a compound of the present invention can be utilized to treat a wide variety of conditions utilizing any number of medical devices, or to enhance the function and/or life of the device.
• intraocular lenses placed to restore vision after cataract surgery is often compromised by the formation of a secondary cataract. The latter is often a result of cellular overgrowth on the lens surface and can be potentially minimized by combining one or more compounds of the present invention having activity that is effective in preventing unwanted cellular growth with the device.
• shunts for hydrocephalus dialysis grafts
• colostomy bag attachment devices colostomy bag attachment devices
• ear drainage tubes ear drainage tubes
• implantable defibrillators can also benefit from the combinations of the compounds of the present invention, possibly other pharmaceutical agents, and the devices.
• any type of medical device can be coated in some fashion with at least one compound of the present invention, alone or as part of a therapeutic agent combination, which enhances treatment over the use of the device or therapeutic agent without combination with the compound.
• the compounds of the present invention can be administered in combinational therapies with other therapeutic agents, and are not limited to only the other therapeutic agents disclosed herein.
• the present invention also contemplates, in addition to various medical devices; the coatings on these devices may be used to deliver a compound of the present invention in combination with other therapeutic agents.
• therapeutic agents can be administered through pharmeutical means or in association with medical devices and such therapeutic agents include, but are not limited to, antiproliferative/antimitotic agents including natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide, teniposide), antibiotics [e.g., dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin], anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP) IIb/IIIa inhibitor
• stents can be utilized in accordance with the present invention, for simplicity, a limited number of stents will be described in exemplary aspects of the present invention. The skilled artisan will recognize that any number of stents can be utilized in connection with the present invention.
• other medical devices can be utilized. For example, though stents are described, sleeves outside the vessels are also contemplated, as are other medical devices that can provide a substrate for administration for at least one of the compounds of the present invention.
• a stent is commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction.
• stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
• a common method of expansion occurs through the use of a catheter-mounted, angioplasty balloon that is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
• a stent may resemble an expandable cylinder and may comprise a fenestrated structure for placement in a blood vessel, duct, or lumen to hold the vessel, duct, or lumen open, more particularly for protecting a segment of artery from restenosis after angioplasty.
• the stent can be expanded circumferentially and maintained in an expanded configuration that is circumferentially or radially rigid.
• the stent can be axially flexible and when flexed at a band, for example, the stent avoids any externally protruding component parts.
• the stent can be fabricated utilizing any number of methods.
• the stent can be fabricated from a hollow or formed stainless steel tube that can be machined using lasers, electric discharge milling, chemical etching, or other means.
• the stent is inserted into the body and placed at the desired site in an unexpanded form.
• expansion can be effected in a blood vessel by a balloon catheter, where the final diameter of the stent is a function of the diameter of the balloon catheter used.
• a stent in accordance with the present invention can be embodied in a shape-memory material including, for example, an appropriate alloy of nickel and titanium or stainless steel.
• Structures formed from stainless steel can be made self-expanding by configuring the stainless steel in a predetermined manner, for example, by twisting it into a braided configuration.
• the stent after the stent has been formed it can be compressed so as to occupy a space sufficiently small as to permit its insertion in a blood vessel or other tissue by insertion means, wherein the insertion means include a suitable catheter, or flexible rod.
• the stent Upon emerging from the catheter, the stent can be configured to expand into the desired configuration where the expansion is automatic or triggered by a change in pressure, temperature, or electrical stimulation.
• a stent can be modified to comprise one or more reservoirs. Each of the reservoirs can be opened or closed as desired. These reservoirs can be specifically designed to hold the compound or compound/therapeutic agent combination to be delivered. Regardless of the design of the stent, the compound or compound/therapeutic agent combination dosage can be applied with enough specificity and a sufficient concentration to provide an effective dosage in the effected area.
• the reservoir size in the bands is preferably sized to adequately apply the compound or compound/therapeutic agent combination dosage at the desired location and in the desired amount.
• the entire inner and outer surface of the stent can be coated with the compound or compound/therapeutic agent combination in therapeutic dosage amounts.
• the coating techniques can vary depending on the compound or compound/therapeutic agent combination. Also, the coating techniques can vary depending on the material comprising the stent or other intraluminal medical device.
• One or more compounds of the present invention and, in some instances, other therapeutic agents as a combination, can be incorporated onto or affixed to the stent in a number of ways.
• the compound is directly incorporated into a polymeric matrix and sprayed onto the outer surface of the stent.
• the compound elutes from the polymeric matrix over time and enters the surrounding tissue.
• the compound can remain on the stent for at least three days up to approximately six months, and, in another aspect, preferably between seven and thirty days.
• the polymeric matrix comprises two layers.
• the base layer comprises a solution of poly(ethylene-co-vinylacetate) and polybutylmethacrylate.
• the compound is incorporated into this base layer.
• the outer layer comprises only polybutylmethacrylate and acts as a diffusion barrier to prevent the compound from eluting too quickly.
• the thickness of the outer layer or topcoat determines the rate at which the compound elutes from the matrix. Essentially, the compound elutes from the matrix by diffusion through the polymer matrix. Polymers are permeable, thereby allowing solids, liquids and gases to escape therefrom.
• the total thickness of the polymeric matrix is in the range from about one micron to about twenty microns or greater. It is important to note that primer layers and metal surface treatments can be utilized before the polymeric matrix is affixed to the medical device. For example, acid cleaning, alkaline (base) cleaning, salinization and parylene deposition may be used as part of the overall process described above.
• the poly(ethylene-co-vinylacetate), polybutylmethacrylate, and compound solution can be incorporated into or onto the stent in a number of ways.
• the solution can be sprayed onto the stent or the stent can be dipped into the solution.
• Other methods include spin coating and plasma polymerization.
• the solution is sprayed onto the stent and then allowed to dry.
• the solution can be electrically charged to one polarity and the stent electrically charged to the opposite polarity. In this manner, the solution and stent will be attracted to one another. In using this type of spraying process, waste can be reduced and more precise control over the thickness of the coat may be achieved.
• Drug-coated stents are manufactured by a number of companies including Johnson & Johnson, Inc. (New Brunswick, N.J.), Guidant Corp. (Santa Clara, Calif.), Medtronic, Inc. (Minneapolis, Minn.), Cook Group Incorporated (Bloomington, Ind.), Abbott Labs., Inc. (Abbott Park, Ill.), and Boston Scientific Corp. (Natick, Mass.). See e.g., U.S. Pat. No. 6,273,913; U.S. Patent Application No. 20020051730; WO 02/26271; and WO 02/26139, each expressly entirely incorporated herein by reference.
• the present invention provides a composition comprising at least one compound as disclosed herein.
• this invention provides a pharmaceutical composition, comprising:
• a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof.
• this invention provides a pharmaceutical composition, comprising:
• a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof;
• the pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch.
• this invention provides a pharmaceutical composition, comprising:
• a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof;
• the pharmaceutical compositions of the present invention can further comprise at least one of any suitable auxiliary such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like.
• suitable auxiliaries are employed. Examples and methods of preparing such sterile solutions are well known in the art and can be found in well known texts such as, but not limited to, R EMINGTON'S P HARMACEUTICAL S CIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)).
• Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the compound.
• compositions for Oral Administration are provided.
• a compound for oral administration in the form of a tablet or capsule, can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture.
• suitable binders include, without limitation, starch; gelatin; natural sugars such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose; polyethylene glycol; waxes; and the like.
• Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
• Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, and the like.
• the invention further relates to the administration of at least one compound disclosed herein by the following routes, including, but not limited to oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, or transdermal means.
• routes including, but not limited to oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabron
• the pharmaceutical compositions can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, or four times daily.
• the daily dosage of the compositions can be varied over a wide range from about 0.0001 to about 1,000 mg per patient, per day. Alternatively, the range can be from about 0.001 mg/kg to about 10 mg/kg of body weight per day, about 0.1 to about 100 mg, about 1.0 to about 50 mg or about 1.0 to about 20 mg per day for adults (at about 60 kg).
• the daily dosage of the pharmaceutical compositions may be varied over a wide range from about 0.01 to about 1000 mg per adult human per day.
• the pharmaceutical compositions can be provided in the form of tablets containing from about 0.1 mg to about 1000 mg of the compound or about 0.1, 0.2, 0.5, 1.0, 2.0, 5.0, 10.0, 15.0, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, or 1000 milligrams of the active compound for the symptomatic adjustment of the dosage to the patient to be treated.
• An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day.
• the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day. In another aspect, the range is from about 0.5 mg/kg to about 10 mg/kg of body weight per day.
• the compounds may be administered on a regimen of about 1 to about 10 times per day.
• co-administration or sequential administration of the compounds of the present invention and other therapeutic agents can be desirable, such as chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, nucleolytic compounds, radioactive isotopes, receptors, and pro-drug activating enzymes, which can be naturally occurring or produced by recombinant methods.
• the combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein there is a time period while both (or all) active therapeutic agents simultaneously exert their biological activities.
• any general structure presented also encompasses all conformational isomers, regioisomers, stereoisomers and tautomers that can arise from a particular set of substituents.
• the general structure also emcompasses all enantiomers, diastereomers, and other optical isomers whether in enantiomeric or racemic forms, as well as mixtures of stereoisomers, as the context requires.
• the general structure also encompasses all salts, including pharmaceutically acceptable and non-pharmaceutically acceptable salts and prodrugs thereof.
• Applicants' intent is to disclose or claim individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein.
• Applicants disclose or claim a chemical moiety having a certain number of carbon atoms Applicants' intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein.
• R is selected independently from an alkyl group having up to 20 carbon atoms, or in alternative language a C 1 to C 20 alkyl group, as used herein, refers to an R group that can be selected independently from a hydrocarbyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, as well as any range between these two numbers for example a C 3 to C 8 alkyl group, and also including any combination of ranges between these two numbers for example a C 3 to C 5 and C 7 to C 10 hydrocarbyl group.
• the molar ratio typically spans the range from about 0.1 to about 1.1
• JP 2004359642 Maleimides as monomers for heat-resistant Nippon Shokubai polymers, and their manufacture Co., Ltd., Japan JP 2004047229 Photoelectric conversion devices using National Institute of electrolyte solutions containing Advanced Industrial aminopyridines, and dye-sensitized solar cells Science and using them Technology, Japan JP 2004018448 Preparation of anhydrous salts of 2′- Mitsui Chemicals A2 20040122 deoxyguanosine derivatives Inc., Japan JP 2002-174770 20020614 WO 2004089910 Preparation of arylpyrazoles as serotonin 5- Merck Patent HT2A and 5-HT2C receptor antagonists GmbH, Germany WO 2004000820 Certain aromatic monocycles, particularly Cellular Genomics, trisubstituted [1,3,5]triazine derivatives, as Inc., USA kinase modulators, and their pharmaceutical compositions and methods of use WO 2003101989 Preparation of pyrazolo[4,3-c]pyridiny
• WO 2003048137 Preparation of 2-phenylbenzoxazoles as Merck & Co., Inc., metabotropic glutamate receptor-5 modulators USA for treatment of pain and CNS disorders
• WO 2003045941 Preparation of pyridine and pyrimidine Celltech R & D derivatives as p38α kinase inhibitors Limited, UK WO 2003029226 Heterocyclyl-substituted phenoxyalkyl-, Basf phenylthioalkyl-, phenylaminoalkyl- and Aktiengesellschaft, phenylalkyl-sulfamoylcarboxamides as Germany herbicides
• WO 2003026664 Preparation of 2-phenylamino-4-(5- Bayer Corporation, pyrazolylamino)pyrimidines as kinase USA inhibitors, in particular, SRC kinase inhibitors
• WO 2003022285 Preparation of substituted 2-(4- Euro-C
• WO 2000043385 Preparation of benzimidazolyltriazine Zenyaku Kogyo derivatives as antitumor agents Kabushiki Kaisha, Japan WO 2000021954 Preparation of 1-benzyl-3-(pyrimidin-2- Bayer yl)indazoles and related compounds as Aktiengesellschaft, stimulators of soluble guanylate cyclase. Germany U.S. Pat. No. 6093734 Preparation of benzimidazole derivatives as USA prodrugs of proton pump inhibitors JP 2000119256 Pyrazolylacrylonitriles and their use as Nissan Chemical agrochemicals Industries, Ltd., Japan U.S. Pat. No.
• 6043242 Preparation of imidazopyridazines for control Byk Gulden of Helicobacter bacteria Lomberg Chemische Fabrik G.m.b.H., Germany WO 9825912 Preparation of herbicidal 1H-tetrazole-1- E. I. Du Pont de carboxamides Nemours & Co., USA; Rorer, Morris Padgett U.S. Pat. No. 6020349 Preparation of thiourea derivatives and related Novo Nordisk A/S, compounds as constrained somatostatin Den. agonists and antagonists U.S. Pat. No.
• DMF dimethylformamide
• BINAP 2R,3S,2,2′-bis-(diphenylphosphino)-1,1′-binapthyl
• DMSO dimethylsulphoxide
• NaH sodium hydride
• CH 2 Cl 2 or DCM dichloromethane
• CDCl 3 deuterated chloroform or chloroform-d
• POCl 3 phosphorus oxychloride
• THF tetrahydrofuran
• AlCl 3 aluminum chloride
• NaOH sodium hydroxide
• Na 2 CO 3 sodium carbonate
• MeOH methanol
• NH 4 OH ammonium hydroxide
• K 2 CO 3 potassium carbonate
• TFA trifluoracetic acid
• SiO 2 silicon dioxide or silica
• KH 2 PO 4 potassium dihydrogen phosphate
• n-BuLi n-butyllithium
• Abbreviations especially frequent in the NMR data are as follows: MHz, megahertz; Hz, hertz; br, broad; apt, apparent; s, singlet; d, doublet; t, triplet; q, quartet; dq, doublet of quartets; dd, doublet of doublets; dt, doublet of triplets; and m, multiplet.
• the precursor compounds such as halogenated pyridines, phenylboronic acid, and substituted phenylboronic acids were obtained from a variety of commercial sources, including, for example, Sigma-Aldrich Inc., Asymchem Laboratories, and Lancaster Synthesis, Inc.
• reaction mixture was extracted three times with diethyl ether.
• the combined organic fractions were washed with 10% sodium thiosulfate solution until it turned light orange in color.
• the organic layer was dried over magnesium sulfate and concentrated on the rotary evaporator, which yielded a light orange solid product (15.4 g, 80%). This material was typically used without further purification.
• a recrystallization may be performed as needed using 3:1 (hexanes:THF). The solid that was formed was filtered and quickly rinsed with cold acetone.
• the CeliteTM was washed with dichloromethane and the filtrate was washed two times with water and one time with brine.
• the organic phase was dried over potassium carbonate and concentrated by rotary evaporation.
• the resulting sample (9) was dried for 12-18 hours under vacuum. The sample was used without purification.
• the resulting product was purified by column chromatography using 230-400 mesh silica gel, eluted with 30:70 ethyl acetate:petroleum ether, to afford the desired compound as light yellow solid (1 g, yield 37%).
• reaction mixture was diluted with CH 2 Cl 2 and filtered through CeliteTM, then rinsed with CH 2 Cl 2 .
• the filtrate was washed two times with water and one time with brine.
• the organic phase was collected and dried over potassium carbonate.
• the filtered sample was concentrated, and the resulting solid was dried for 12-18 hours under vacuum.
• the reaction mixture was diluted with CH 2 Cl 2 and filtered through CeliteTM, then rinsed with CH 2 Cl 2 .
• the filtrate was washed two times with water and one time with brine.
• the organic phase was collected and dried over potassium carbonate.
• the filtered sample was concentrated, and the resulting solid was dried for 12-18 hours under vacuum.
• Biotage Horizon HPFC system chromatography SiO 2 , 50:50 hexanes:ethyl acetate
• This compound was prepared by the process disclosed in Example 37.
• This compound was prepared by the process disclosed in Example 37.
• This compound was prepared by the process disclosed in Example 37.
• This compound was prepared by the process disclosed in Example 37.
• This compound was prepared by the process disclosed in Example 37.
• IR (neat) cm ⁇ 1 2917, 1603, 1435, 1225, 1152, 987, 955, 824, 779, 562.
• This compound was prepared by at least one of the processes disclosed in Examples 54-55, and could be prepared by both of the processes disclosed in these examples.
• the reaction mixture was diluted with CH 2 Cl 2 and filtered through CeliteTM, then rinsed with CH 2 Cl 2 .
• the filtrate was washed two times with water and one time with brine.
• the organic phase was collected and dried over potassium carbonate.
• the filtered sample was concentrated, and the resulting solid was dried for 12-18 hours under vacuum. Flash chromatography (SiO 2 , 93:6:1 CH 2 Cl 2 :MeOH:NH 4 OH) yielding a light yellow solid (83 mg, 17%).
• This compound was prepared by a method analogous to that disclosed in Example 52.
• This compound was prepared by a method analogous to that disclosed in Example 52.
• This compound was prepared by a method analogous to that disclosed in Example 52.
• the resulting reaction mixture was refluxed for 10 hours, after which time water was added 100 mL to the reaction mixture, and the product was extracted with ethyl acetate (100 mL ⁇ 3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (20:80 acetone:petroleum ether) to afford the desired compound (75 mg, purity 99%, yield 6%.).
• IR (neat) cm ⁇ 1 3408, 2935, 1607, 1590, 1449, 1261, 1157, 1018, 921, 844, 812.
• IR (neat) cm ⁇ 1 2940, 1597, 1556, 1506, 1451, 1263, 1223, 1152, 986, 922.
• IR (neat) cm ⁇ 1 3362, 2926, 1619, 1595, 1533, 1506, 1464, 1416, 1296, 1251, 1244, 1196, 1149, 1128, 966, 824, 795.
• IR (neat) cm ⁇ 1 3387, 2934, 1613, 1584, 1508, 1462, 1331, 1223, 1153, 1093, 819.
• the resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL ⁇ 3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (20:80 acetone:petroleum ether) to afford the desired compound pale yellow solid (46 mg, yield 34%.).
• IR (neat) cm ⁇ 1 3254, 2925, 1618, 1600, 1524, 1326, 1220, 1153, 1092, 979, 917, 856.
• the resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL ⁇ 3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (elution 2:98 methanol:DCM) to afford the desired compound pale yellow solid (30 mg, yield 30%.).
• IR (neat) cm ⁇ 1 3386, 2920, 1615, 1450, 1302, 1153, 1015, 959, 832.
• This compound was prepared by a process analogous to that disclosed in Example 63.
• This compound was prepared by a process analogous to that disclosed in Example 63.
• IR (neat) cm ⁇ 1 3380, 2925, 1595, 1506, 1452, 1261, 1160, 813.
• This compound was prepared by a process analogous to that disclosed in Example 63.
• IR (neat) cm ⁇ 1 2938, 1607, 1550, 1506, 1449, 1260, 1203, 1162, 1017, 921, 807.
• This compound was prepared by a procedure analogous to that disclosed in Example 73.
• This compound was prepared by a procedure analogous to that disclosed in Example 73.
• This compound was prepared by a procedure analogous to that disclosed in Example 73.
• This compound was prepared by a procedure analogous to that disclosed in Example 73.

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